Effects of adenosine A_2A receptor stimulation on cocaine-seeking behavior in rats

Rationale: Dopamine (DA) receptor stimulation in the nucleus accumbens (NAc) plays an important role in regulating cocaine-seeking behavior. Adenosine receptors antagonize the effects of DA receptor stimulation on intracellular signaling, neuronal output, and behavior. Objectives: The goal of the present study is to determine the effects of adenosine A_2A receptor stimulation on reinstatement of cocaine-seeking behavior in rats. Methods: Rats were trained to lever press for cocaine in daily self-administration sessions on a fixed-ratio 1 schedule for 3 weeks. After 1 week of abstinence, lever pressing was extinguished in six daily extinction sessions. We subsequently assessed the effects of the adenosine A_2A receptor agonist, CGS 21680, on cocaine-, quinpirole (D₂ agonist)-, and cue-induced reinstatement to cocaine seeking. We also assessed the effects of CGS 21680 on sucrose seeking in rats extinguished from sucrose self-administration. Results: Pretreatment of CGS 21680 dose-dependently blunted cocaine-induced reinstatement (15 mg/kg, i.p.). Pretreatment with CGS 21680 (0.03 mg/kg, i.p.) also attenuated quinpirole- and cue-induced reinstatement. A minimally effective dose of CGS 21680 failed to alter cocaine-induced locomotor activity or sucrose seeking. Conclusions: Stimulation of adenosine A_2A receptors antagonizes reinstatement of cocaine seeking elicited by cocaine, DA D ₂-receptor stimulation, and cocaine-conditioned cues. These findings suggest that adenosine A_2A receptor stimulation may oppose DA D ₂ receptor signaling in the NAc that mediates cocaine relapse.